Tag: Mitochondria

The road ahead: 2025 (part 1)

~ Simon ~ 5 Comments

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The first post at the start of each year on the SoPD website has traditionally tried to provide an overview or some context on where things are in the search for ‘disease modifying’ therapies for Parkinson’s. 

Previous editions of the “Road Ahead” posts have become dangerously overloaded, unwieldy, chaotic one-page beasts, so this year we are shifting to a multi-post format, which will hopefully provide the reader with less of a burdensome shopping list of novel therapies and more of a digestible piece of information (famous last words – be warned, this is still a very long post!).  

In this first post, we will look at the latest developments that have resulted from the biology associated with Parkinson’s-related genetic risk factors (this is a long post – click here if you would like to skip the introduction and go straight to the table of contents)

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A future historian? Source: Inc

When future academics sit down to write the history of the condition that we currently know of as “Parkinson’s”, they may well look upon 1997 as a key turning point for what came next.

Why 1997? What happened then? And what came next?

On the morning of 27th June, 1997, the prestigious scientific journal ‘Science’ went to press, highlighting a research report that would change the world of Parkinson’s forever.

And I am not exaggerating here – the impact of the study was (and still is) truly profound.

The paper reported the discovery of tiny variations in a region of human DNA that scientists refer to as the “alpha synuclein” gene, and it explained that these genetic errors could significantly increase one’s risk of developing Parkinson’s. The scientists had made this finding across large Italian and Greek families that exhibited very high incidences of Parkinson’s (Click here to read a previous SoPD post on this discovery):

Science

Title: Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease.
Authors: Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL.
Journal: Science. 1997 Jun 27;276(5321):2045-7.
PMID: 9197268

And then – remarkably just two months later – the results of another study were published in the scientific journal ‘Nature’ that would further cement alpha synuclein’s place in Parkinson’s research.

In this second research paper, the investigators showed that a particular protein was highly enriched in “Lewy bodies” – dense spheres of protein inside of cells that are one of the characteristic features of the Parkinsonian brain. That protein was the very same one that is produced by the instructions provided by the alpha synuclein gene:

Title: Alpha-synuclein in Lewy bodies.
Authors: Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M.
Journal: Nature. 1997 Aug 28;388(6645):839-40.
PMID: 9278044

And so it was that alpha synuclein became ‘public enemy #1’ in the world of Parkinson’s research. After decades of research, scientist finally had their ‘foot in the door’ in terms of the biology that could potentially be underlying the condition.

What came next can only be described as a ‘gold rush’ in Parkinson’s research, with genetic risk factors in other regions of DNA suddenly being associated with Parkinson’s. In 1998, genetic variations in one called the “PARKIN” gene were discovered, then in 2003 it was the turn of “DJ-1″, followed the year after by the “LRRK2″ and “PINK1″ genes.

Today we know of approximately 80 genetic regions believed to be influencing the risk of developing Parkinson’s:

Nalls et al (2019). Source: PMC

While all of this research focused on variation in our DNA does not mean that Parkinson’s is a genetic condition (please note that these variations are only found in about 15-20% of the PD affected community and infer vulnerability rather than certainty), the truly crucial aspect of these discoveries has been learning about the associated biology.

What do you mean by “associated biology”?

Continue reading “The road ahead: 2025 (part 1)” →

Exploring the damage of mtDNA

~ Simon ~ 4 Comments

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Mitochondria are curious little structures that live symbiotically within cells. They are believed to derive from an ancient bacterial past, and they still retain elements of that forgotten occupation: They have their own DNA.

Given that mitochondria are very metabolically active, that mitochondrial DNA can be vulnerable to damage.

Recently, researchers have proposed that damage to mitochondrial DNA might be a useful biomarker for Parkinson’s.

In today’s post, we will look at what mitochondria do, what damage to their DNA means, and how this could be very useful for our understanding of Parkinson’s.

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Source: Szegedify

In Chinese culture, 2023 has been in the Year of the Rabbit.

The Rabbit is a symbol of longevity, peace and prosperity. As such, 2023 is predicted to be a year of hope.

Here at SoPD HQ, we think 2023 has been the Year of the Biomarker.

Think about it. Over the course of this year, we have covered a couple of new reports proposing the alpha synuclein seeding assay (Click here to read more about this) and DOPA decarboxylase levels in cerebrospinal fluid as potentially useful markers for Parkinson’s (Click here to read more about this).

And recently, researchers have proposed another biomarker which involves an important aspect of Parkinson’s associated biology: Mitochondria.

Remind me: What are mitochondria?

Continue reading “Exploring the damage of mtDNA” →

Getting a handle on Miro1

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Novel therapeutic interventions are being proposed for Parkinson’s on a regular basis, with compelling data supporting their future development.

The case is strengthened when a measure of target engagement is also involved – providing not only a potential therapy but also a biomarker as well.

Recently, a biotech company called AcureX Therapeutics has been presenting just such a case, based on a biological mechanism involving the protein Miro1.

In today’s post, we will discuss what Miro1 is and how it might be useful for future clinical trials.

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Watching the recent Michael J Fox Foundation‘s Progress in the PD Pipeline webinar (Wednesday 10th November, 2021), I was really impressed by the presentation by Dr Bill Shrader (co-founder and CEO/CSO of AcureX Therapeutics)

 

In particular, I really liked their approach to potential patient selection for future clinical trials of their lead drug candidate. It all revolves around the analysis of Miro1 as a biomarker.

What is Miro1?

Continue reading “Getting a handle on Miro1” →

Turn back Bach?

~ Simon ~ 2 Comments

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Cellular activity generates a lot of waste and by-products. Cells have developed very efficient methods of dealing with this situation.

As we age, however, these processes become strained, and in degenerative conditions they appear to be rather dysfunctional. 

New research highlights a novel mechanism – Bach1 derepression – which points towards a new class of potential therapeutics and interesting avenues of further study.

In today’s post, we will discuss the results of this new research and explore the implications of it.

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Source: Maxpixel

I am marveling at the fact that I am typing these words.

And that you are reading them.

Consider for a moment the requirements of this arrangement. And I’m not talking about the tiny muscles changing the size of the pupil in your eye, or the neurons in your visual cortex firing in unison to give you a correct and colour-rich representation of the world in front of you that has nothing to do with the actual content being observed.

Rather, I’m thinking more about about what is going on one level down – actually inside of each cell:

A liver cell. Source: Muhadharaty

There is a universe of frenzied molecular activity in each and every cell of our bodies. And we are only just starting to build up a user guide to the densely packed, fuzzy complexity of this inner world. This video gives an extremely simplified version of some of what is going on (in reality, the interior of cells is significantly more densely packed and the activity is a vastly quicker):

https://www.youtube.com/watch?v=VdmbpAo9JR4

And as I suggested above it should be celebrated that what occurs in these cells is so rapid, efficient and precise that I can type these words and you can read them.

All of this crazy activity, however, produces waste and by-products.

Cells have of course developed very effective means of dealing with those issues. But as we age, cells can start to struggle with the task of waste disposal. And as a result, we can start to see an accumulation of these by-products, which can lead to stress on the cell, particularly in the form of oxidative stress.

What is oxidative stress?

Continue reading “Turn back Bach?” →

PARP-kinson’s goes chlorogenic

~ Simon ~ 4 Comments

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For a long time it was been reported that coffee may be able to reduce the risk of developing Parkinson’s, but the mechansim by which this association could be occurring has remained elusive.

Now researchers from South Korea have discovered a biological pathway that could help to explain the protective association.

It involves a protein called PARP and a chemical called chlorogenic acid.

In today’s post, we will explore the research suggesting a link between coffee and a lower risk of Parkinson’s, discuss what PARP and chlorogenic acid are, and review the new research that may bring all four topics together.

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kaldi-adapted-from-uker

Kaldi the goat herder. Source: CoffeeCrossroads

Legend has it that in 800AD, a young Ethiopian goat herder named Kaldi noticed that his animals were “dancing”.

They had been eating some berries from a tree that Kaldi did not recognise, but being a plucky young fellow – and being fascinated by the merry behaviour of his four-legged friends – Kaldi naturally decided to self-experiment by eating some of the berries for himself.

The result?

He became “the happiest herder in happy Arabia” (Source).

This amusing encounter was apparently how humans discovered coffee. It is most likely a fiction as the earliest credible accounts of coffee-consumption emerge from the 15th century in the Sufi shrines of Yemen, but since then coffee has gone on to become one of the most popular drinks in the world.

coffee-cup-images-5

Fancy a cuppa? Source: Science-All

Interesting, but what does coffee have to do with Parkinson’s?

Continue reading “PARP-kinson’s goes chlorogenic” →

A PINK shade of inflammation

~ Simon ~ 5 Comments

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Inflammation is the means by which tissue in our bodies communicate with the immune system to indicate when something is wrong. Tiny messenger proteins are released from stressed or damaged cells to alert neighbouring cells of their situation.

Ailing cells can also release additional components – such as DNA – that can activate immune cells and cause inflamation.

Recently, researchers have identified both messenger proteins and specific types of DNA that are present in the blood of individuals with a genetically-associated sub-type of Parkinson’s. The discovery could provide both novel biomarkers, but also point towards specific biological pathways that could be therapeutically targetted.

In today’s post, we will review this new research.

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Ouch! Source: MedicalExpress

When cells in your body are stressed, damaged, or sick, they begin to release large amounts of tiny messenger proteins which inform the rest of your body that something is wrong.

When enough of these messenger proteins are released, cells of the immune system will become activated, and come looking for the source of the trouble.

This is inflammation.

Source: Youtube

Inflammation is a critical part of the immune system’s response to problems. It is the body’s way of communicating with the immune system and explaining that something is wrong. This also aid in activating the immune system so that it can help deal with the situation.

By releasing the messenger proteins (called cytokines), injured/sick cells kick off a process that results in multiple types of immune cells entering the troubled area of the body and undertaking very specific tasks.

The inflammatory process. Source: Trainingcor

The strength of the immune response depends on the volume of the signal arising from those released messenger proteins.

For a long time, it has been hoped that some of these messenger proteins might be useful as biomarkers for conditions like Parkinson’s. And recently, researchers have published data suggesting that they might have found one cytokine that could be very useful for a specific sub-set of people with Parkinson’s.

What did they find?

Continue reading “A PINK shade of inflammation” →

When miro just can’t let go

~ Simon ~ 20 Comments

 

Stanford University researchers have recently published an interesting report in which they not only propose a novel biomarker for Parkinson’s, but also provide some compelling data for a novel therapeutic approach.

Their research focuses on a protein called Miro, which is involved in the removal of old or faulty mitochondria. Mitochondria are the power stations of each cells, providing cells with the energy they require to do what they do.

Specifically, the researchers found that Miro refuses to let go of mitochndria in people with Parkinson’s (which could act as a biomarker for the condition). They also found that pharmacologically forcing Miro to let go, resulted in neuroprotective benefits in models of Parkinson’s

In today’s post, we will discuss what Miro is, what the results of the new research suggest, and we will consider what will happen next.

 

 

Source: Amazingaccelerators

Every now and then a research report comes along and you think: “Whoa, that’s amazing!”

It a piece of work that breaks down your cynicism (which you have proudly built up over years of failed experiments) and disciplined scepticism (a critical ingredient for a career in scientific research – mantra: ‘question everything’). And for a moment you are taken in by the remarkable beauty of not just good research, but biology itself.

A couple of weeks ago, one such research report was published.

This is it here:

Title: Miro1 Marks Parkinson’s Disease Subset and Miro1 Reducer Rescues Neuron Loss in Parkinson’s Models.
Authors: Hsieh CH, Li L, Vanhauwaert R, Nguyen KT, Davis MD, Bu G, Wszolek ZK, Wang X.
Journal: Cell Metab. 2019 Sep 23. [Epub ahead of print]
PMID: 31564441

It’s a really interesting study for several reasons.

So what did they report?

Continue reading “When miro just can’t let go” →

WPC 2019 – Day 3

~ Simon ~ 7 Comments

 

Today’s post is a recap of Day 3 – the final day – at the World Parkinson’s Congress meeting in Kyoto, Japan.

I will highlight some of the presentations I was able to catch and try to reflect on what was an amazing meeting.

 

The final day of the WPC meeting for me started with Parkinson’s advocate Heather Kennedy‘s presentation on “Your radical new life: Creative ways to overcome our challenges”. In her talk, she spoke of the mindset that is required for tackling Parkinson’s and provided some advice on what-to-do and what-not-to-do.

And Heather was speaking from personal experience. Having been diagnosed in 2012, she has become an active advocate, supporter of Davis Phinney and Michael J Fox Foundations, and an administrator on several online sites. And she regularly speaks about different methods for overcoming the challenges of Parkinson’s:

“It is not ‘why is this happening to me?’, it is ‘what is this teaching me?”

Here is a presenation she gave at the recent Parkinson’s Eve meeting in the UK earlier this year:

Key among her pieces of advice is the need to make connections:

Continue reading “WPC 2019 – Day 3” →

Deep Mitochondrial stimulation?

~ Simon ~ 7 Comments

 

 

Recently some researchers conducted an analysis of some postmortem brains from people with Parkinson’s and they discovered something rather curious.

Half of the brains that they analysed came from people with Parkinson’s who had been given deep brain stimulation (or DBS) to help manage their symptoms. When the researchers analysed the mitochondria – the powerstations of each cell – in the dopamine neurons of these brain, they found that the DBS treatment had helped to improve the number of mitochondria in these cells.

Specifically, the DBS treatment “seemed to have inhibited or reversed the reduction in mitochondrial volume and numbers” that was observed in the Parkinson’s brains that had not had DBS.

In today’s post, we will look at what DBS is, what the new research report found, and what these new findings could mean for the Parkinson’s community.

 

The worst thing. Source: Greatist

Do you know the worst thing that happens to us in life?

We wake up each day.

Every day of our lives (so far) we have woken up and been given – without any kind of justification – another 16 or so hours to do whatever we want with.

Regardless of one’s physical/mental state, this is a bad thing.

This continuous pattern is what is referred to in psychology as a ‘continuous schedule of reinforcement’. Such regimes instill complacency and – worse – expectation. They quickly lead to people taking things for granted. All of us are guilty of thinking “I’ll do it tomorrow”.

Source: Taskcracker

Such a continuous pattern of reinforcement does not prepare one well for a life in scientific research, where there isn’t a constant schedule of reinforcement (quite the opposite actually). Experiments regularly go wrong (reagents/equipment fail), grants/manuscripts get rejected – it can be rather brutal.

But here is where the addictive component of science comes into effect. Every so often, something works. And even better, every so often something unexpected happens – an ‘intermittent/irregular schedule of reinforcement’. An experiment will occasionally spit out a completely unexpected result, which could change everything.

Source: Granger

These are the moments of insights that researchers are slaving for. The instant that they are the first to “walk on the moon”.

They are moments to savour.

And this must have been the state of mind for some researchers who dicovered something surprising and absolutely remarkable recently while they were looking at some postmortem brains from individuals with Parkinson’s who had been treated with deep brain stimulation.

What is deep brain stimulation?

Continue reading “Deep Mitochondrial stimulation?” →

The UP Study – UDCA in Parkinson’s

~ Simon ~ 15 Comments

 

Today we received word of a new clinical trial for Parkinson’s being initiated here in the UK. This trial – named the UP study – will evaluate the safety and tolerability of a compound called Ursodeoxycholic acid (or UDCA – click here to read the press release).

UDCA is clinically available medication that is used in the treatment of gall stone, but recently there has been a large body of research suggesting that this compound may also have beneficial effects in Parkinson’s.

In today’s post, we will look at what UDCA is, discuss the preclinical research exploring UDCA, and outline the structure of the new clinical trial.

 

Source: Youtube

How often do you consider your gallbladder?

It is one of the less appreciated organs. A pear-shaped, hollow organ located just under your liver and on the right side of your body. Its primary function is to store and concentrate your bile. What is bile you ask? Bile is a yellow-brown digestive enzyme – made and released by the liver – which helps with the digestion of fats in your small intestine (the duodenum).

Source: Mayoclinic

One of the down sides of having a gall bladder: gallstones.

Gallstones are hardened deposits that can form in your gallbladder. About 80% of gallstones are made of cholesterol. The remaining 20% of gallstones are made of calcium salts and bilirubin. Bilirubin is the yellow pigment in bile. When the body produces too much Bilirubin or cholesterol, gallstones can develop.

Gallstones – ouch! Source: Healthline

About 10-20% of the population have gallstones (Source), but the vast majority experience no symptoms and need no treatment.

Interesting intro, but what does any of this have to do with Parkinson’s or a new clinical trial?

One of the treatments for gallstones is called UDCA. And today we found out that this compound is being clinically tested for “repurposing” as a treatment for Parkinson’s.

What is UDCA?

Continue reading “The UP Study – UDCA in Parkinson’s” →